A theoretical model for attachment lifetimes of kinetochore-microtubules: Mechano-kinetic "catch-bond" mechanism for error-correction

TL;DR

This paper presents a detailed microscopic model explaining how kinetochore-microtubule attachments exhibit catch-bond behavior, with implications for error correction during cell division.

Contribution

It introduces the first microscopic model for MT-kinetochore attachment lifetimes, capturing the mechano-kinetic catch-bond mechanism observed experimentally.

Findings

The model reproduces non-monotonic lifetime dependence on tension.

In-silico experiments predict new phenomena for experimental testing.

The catch-bond mechanism emerges naturally from the model's structure.

Abstract

Before cell division, two identical copies of chromosomes are pulled apart by microtubule (MT) filaments that approach the chromosomes from the opposite poles a mitotic spindle. Connection between the MTs and the chromosomes are mediated by a molecular complex called kinetochore. An externally applied tension can lead to detachment of the MTs from the kinetochore; the mean lifetime of such an attachment is essentially a mean first-passage time. In their in-vitro pioneering single-kinetochore experiments, Akiyoshi et al. (Nature 468, 576 (2010)), observed that the mean lifetimes of reconstituted MT-kinetochore attachments vary non-monotonically with increasing tension. The counter-intuitive stabilization of the attachments by small load forces was interpreted in terms of a catch-bond-like mechanism based on a phenomenological 2-state kinetic model. Here we develop the first detailed microscopic model for studying the dependence of the lifetime of the MT-kinetochore attachment on (a) the structure, (b) energetics, and (c) kinetics of the coupling. The catch-bond-like mechanism emerges naturally from this model. Moreover, in-silico experiments on this model reveal further interesting phenomena, arising from the subtle effects of competing sub-processes, which are likely to motivate new experiments in this emerging area of single-particle biophysics.